Persistent mucosal damage and risk of epilepsy in people with celiac disease.

BACKGROUND AND PURPOSE: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. METHODS: This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. RESULTS: Villous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). CONCLUSIONS: In a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

[Rabeprazole induced acute interstitial nephritis]. / Néphropathie tubulo-interstitielle aiguë au cours d'un traitement par le rabéprazole (Pariet).

A 84-year-old women underwent renal biopsy because of rapidly progressive renal failure. Rabeprazole induced interstitial nephritis was diagnosed. Interstitial nephritis may complicate the course of any proton pump inhibitor treatment. It is a rare and serious complication. Clinician's awareness of this adverse event is essential for early diagnosis and prompt recovery.

In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA.

Hepatitis B virus (HBV) is a small DNA virus with a compact genomic organization. All HBV proteins identified to date have been encoded by unspliced HBV RNAs. Spliced HBV RNAs have been described, but their functions are unknown. We show here that a singly spliced HBV RNA encodes a novel HBV protein in vivo. This HBV splice-generated protein (HBSP) corresponds to the fusion of a part of the viral polymerase and a new open reading frame that is created by the splicing event. In vivo, HBSP protein was found in HBV-infected liver samples, and anti-HBSP antibodies occurred in one-third of sera samples collected from chronic HBV carriers. In vitro, the ectopic expression of HBSP had no effect on viral DNA replication or transcription but induced cell apoptosis without a cell-cycle block. Overall, our results suggest that HBV has evolved a mechanism that directly modulates virus-cell interaction through RNA splicing.

Inflammatory cytokines and inhibitors in HIV infection: correlation between interleukin-1 receptor antagonist and weight loss.

OBJECTIVE: To determine serum levels of the interleukin-1 receptor antagonist (IL-1Ra), together with cytokines, other cytokine inhibitors and markers of immune activation in HIV-infected patients. METHODS: Sixty-one HIV-patients were classified into Center for Disease Control and Prevention (CDC) groups A (n = 14), B (n = 14) and C (n = 33). Serum levels of IL-1Ra, IL-1 beta, IL-6, tumour necrosis factor (TNF-alpha, TNF soluble receptors (TNF-sR) and IL-2sR were measured by enzyme-linked immunosorbent assay. CD4+ cell counts, p24 antigen, immunoglobulin (Ig) A, beta 2-microglobulin, triglycerides and neopterin were measured according to standard procedures. Weight variation was measured as the percentage of baseline weight lost or gained during the 3 months before sampling. RESULTS: Serum levels of IL-1Ra were significantly elevated in HIV-infected patients, compared with control subjects (S47 +/- 104 and 133 +/- 7 pg/ml), but did not vary significantly with the HIV disease stage, CD4+ cell count or p24 antigenaemia. IL-1Ra levels correlated with IL-1 beta (P < 0.005), IL-6 (P < 0.0001) and TNF-sR55 (P < 0.0001) levels, but not with those of TNF-alpha, TNF-sR75, IL-2sR, neopterin or IgA. IL-1 Ra and IL-1 Ra/IL-1 beta ratio were the only parameters significantly elevated (R = -0.67, P < 0.0001) in the HIV-infected patients with marked weight loss (n = 12; mean of weight variation, -13.9 +/- 2.1% relative to the other patients, regardless of HIV disease stage and opportunistic infections. CONCLUSIONS: IL-1Ra levels are significantly elevated in HIV infected patients, independently of immune deficiency. We propose that IL-1Ra accumulates in intense systemic inflammation, a state which does not seem to be reflected by the elevation of a single cytokine or the activation at a single cell system and which is correlated with marked weight loss.

Hepatitis C virus-related fibrosing cholestatic hepatitis after renal transplantation.

Fibrosing cholestatic hepatitis is a well-described syndrome in patients with immunodeficiency and chronic hepatitis B. It is clinically, biologically, and histologically characterized by rapidly progressive hepatic failure, a mildly elevated serum aminotransferase level, an extensive periportal fibrosis associated with intense cholestasis, mild inflammatory cellular infiltrate, no cirrhosis, and a high hepatocellular level expression of B viral antigens. This syndrome reflected a direct hepatocytopathic injury linked to high intrahepatic viral antigen expression. Because the syndrome of fibrosing cholestatic hepatitis has not been described in chronic hepatitis C, we report the first well-characterized case in a renal transplant patient with chronic hepatitis C and discuss the clinical and pathogenic implications of such a syndrome in this setting.

HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients.

BACKGROUND: Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients. METHODS: We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations. RESULTS: Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region. CONCLUSION: We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.

Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C.

To analyze the spontaneous pathologic progression of chronic hepatitis C, we analyzed the histopathologic semiquantitative scores (Metavir and Knodell) of sequential liver biopsies performed in untreated hepatitis C virus (HCV)-infected patients. Subjects included 35 men and 41 women, with a mean age of 41 +/- 12 years, a duration of HCV infection of 11 +/- 5 years, and an interval between liver biopsies of 3.7 +/- 2.5 years. Results obtained using the Knodell score and the Metavir score were similar. At the first biopsy, 78.9% of patients had a low activity score (A0-A1) and 82.9% had a low fibrosis score (F0-F2). At the second biopsy, the activity decreased in 9.2%, was unchanged in 72.4%, and increased in 18.5%. An increase in activity was more frequently observed in patients infected with genotype 1 (28.9%) than with others (7.7%; P =.04); the yearly progression of activity was significantly higher in patients with a low rather than high initial activity score (0.11 v -0.02; P <.01). An increase in fibrosis was noted in 13.3% of those with a low and 43.8% of those with a high initial activity score (P <.01), with a highest rate of yearly fibrosis progression (0.12 U). In multivariate analysis, only a high activity score was significantly associated with an increased risk of fibrosis progression (relative risk, 25.5; 95% confidence interval, 2.7 to 238; P =.004). Spontaneous chronic hepatitis C evolution is worsening in only 20% of patients. Fibrosis progression is significantly associated with the necroinflammatory activity suggesting that this factor should be regarded as a major clue for deciding therapy.

Characteristics and treatment of hepatitis C virus infection in HIV-coinfected subjects.

Hepatitis C virus (HCV) and HIV share the same parenteral routes of transmission. This common epidemiology explains the high frequency of combined infections by HCV and HIV. The aim of this review is to clarify some important issues dealing with the reciprocal impact of HIV and HCV-associated infections, including the variations in clinical, biologic, histopathologic, and virologic natural history of both infections. Insights gained may improve clinical care of and the therapeutic approach to HCV infection in HIV-coinfected subjects.

[Porto-hepatic thrombosis, revealing paroxysmal nocturnal hemoglobinuria, followed by regression induced by heparin therapy]. / Double thrombose porte et hépatique révélatrice d'une hémoglobinurie paroxystique nocturne et régressive sous héparinothérapie.

Budd-Chiari syndrome with or without portal thrombosis occurring during paroxysmal noctural hemoglobinuria is a complication with poor prognosis. We report the case of a 17-year-old woman with a double portal and hepatic venous thrombosis revealing a paroxysmal noctural hemoglobinuria and regressive with heparin. Our case suggests that the early diagnosis of the thrombosis with ultrasonography and Doppler, and rapidly initiated anticoagulant treatment may improve the prognosis of this disease.

Alpha-interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients.

OBJECTIVES: A pilot study was conducted to evaluate the efficiency of alpha-interferon treatment in chronic active hepatitis B in anti-HIV-positive patients. METHODS: Twenty-five patients with chronic active hepatitis (23 men and 2 women, mean age: 33 years) were included in the study. Viral infections were acquired by intravenous drug addiction in 2, homosexual relations in 22, and multiple heterosexual contacts in one. The mean CD4 cell count was 480 +/- 234/mL, 7 patients had p24 antigenemia, but none belonged to class C of the CDC classification. All patients were serum HBs Ag and HBV DNA-positive, and delta antigen and antibody negative. Patients received a 6-month course of alpha-interferon 2a, 6 MU subcutaneously three times per week. The mean follow-up after treatment was 15 months. Eighteen patients with serum anti-HIV antibodies, HBsAg and HBV DNA-positive, and chronic active hepatitis, who were not treated with interferon, were included as controls (mean follow-up: 29 months). RESULTS: Nine of the 25 patients (36%) lost serum HBV DNA (1, 2, 4, 6, and 8 months after the beginning of treatment in 1, 4, 1, 2 and 1 cases, respectively), and were considered responders. Only one of the responders developed serum anti-HBe during follow-up, despite the disappearance of HBe Ag in 2 and of HBs Ag in one. Loss of HBV DNA was not clearly associated with the immune status, since 3 of the 9 responders had p24 antigenemia and the 9 responders had a lower mean CD4 count (283 +/- 246/mm3) than non responders (454 +/- 437/mm3, NS). Three of the 18 patients (16.7%) in the control group had spontaneous loss of serum HBV DNA during follow-up. Thus, there was a 2.15-fold increase in HBV DNA loss in the anti-HIV-positive patients who received alpha-interferon, compared to those who did not. CONCLUSION: In HIV-positive patients treated with alpha-interferon, the rate of HBV DNA loss was not clearly different from that reported in immunocompetent patients. As severe HBV-related liver disease has previously been described in anti-HIV positive patients, at least in drug users, these results suggest that this treatment may be proposed whatever the immune status, at least in the absence of AIDS.

[Prevalence of infection by hepatitis viruses in a rural area. Analysis according to risk factors and alcohol consumption]. / Prévalence des infections par les virus hépatotropes en milieu rural. Analyse en fonction des facteurs de risque viraux et de la consommation d'alcool.

OBJECTIVES: To evaluate the prevalence of serum markers of hepatitis A, B and C viruses in a rural area according to risk factors and alcohol consumption. METHODS: Transversal study of unselected subjects living and working in a rural area. Each subject included was asked to fill out an anonymous self-administered questionnaire dealing with his own risk factors, sexual behaviour and alcohol consumption. A blood sample was collected for detection of HBsAg, anti-HBc, anti-HBs, anti-HAV and anti-HCV antibodies. RESULTS: Three hundred three subjects with a mean age of 48 years were included. Main risk factors for viral infection were: blood transfusion (9.4%), intravenous drug addiction (0.73%), acupuncture (17.5%), tattoos (5. 8%), past hospitalizations (71.5%), homosexuality (1.1%), conjugal unfaithfulness (11%), sexual partners >5 (21.3%). Most subjects with at risk sexual behaviour had sexual relations without protection. Anti-HAV prevalence was 87.2% (95% confidence interval 83.4-91.0%). None of the subjects was HBsAg positive and 6.0% (confidence interval 4.7-8.7%) had anti-HBV antibodies. HBV prevalence was correlated to homosexuality only. Two subjects (0.67%, confidence interval 0-1.6%) without any identified risk factor had anti-HCV antibodies. There was no correlation between serum viral marker positivity and an excess alcohol consumption (>80 g of ethanol/d) which was present in 46 subjects. However HBV prevalence was 28.6% in the seven subjects who had been treated for alcoholism; these 7 subjects had a highly at risk sexual behaviour. CONCLUSION: In a rural area, infection by HAV is very frequent. The prevalence of HBV and HCV did not greatly differ from that observed in the general and urban population. The frequent failure to use protection in subjects with at risk sexual behaviour reinforces the need of prevention programs in rural areas.

[Interactions between the human immunodeficiency virus and hepatitis C virus]. / Interactions entre les virus de l'immunodéficience humaine et de l'hépatite C.

INTRODUCTION: Prevalence of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected subjects is around 9%, varying according to the mode of contamination. Reciprocal interactions between the two viruses have to be evaluated. CURRENT KNOWLEDGE AND KEY POINTS: HCV infection is usually associated with chronic hepatitis and detectable viremia in HIV-infected patients. HIV infection enhances HCV replication, leading to more severe liver lesions and to a more rapid occurrence of cirrhosis. This underlines the need for both early diagnosis and therapy in order to avoid severe evolution of the liver disease. FUTURE PROSPECTS AND PROJECTS: Even though the rate of long-term responses to interferon alpha is low, improvement may be expected from combined therapies, especially with combination including ribavirin. The impact of both antiretroviral triple therapy and accompanying immune restoration on natural history and treatment of HCV infection has to be assessed, as the above mentioned consensual conclusions may be modified in a near future.

[Clinical forms and prognosis of hepatitis C]. / Formes cliniques et évolution de l'hépatite C.

Hepatitis C virus infects around 600,000 French people, mainly after parenteral exposure (in association with transfusion before 1990 and with intravenous drug use). Spontaneous resolution at the acute stage of the infection occurs in around 30% of cases while chronic infection is observed in around 70% of cases and its main risk is evolution to cirrhosis. Three predictive factors of cirrhosis have been identified: the duration of infection (greater than 20 years), the age at contamination (greater than 40 years) and a chronic alcohol consumption (> 80 g/day). Immunosuppressive situations (drug-related immune suppression for the prevention of graft rejection in allograft recipients or human immune deficiency virus-coinfection) as well as hepatitis B virus coinfection enhance the risk of cirrhosis and reduce the time of occurrence of cirrhosis. These predictors have to be considered in the information to the patients and in therapeutic decisions. They explain that any hepatitis C virus-infected patient has to undergo a liver biopsy to evaluate the necro-inflammatory activity and the fibrosis of the liver disease to delineate the place of a follow-up with a control of aggravation factors (alcohol discontinuation) and of an antiviral therapy.